This invention was made with government support under agreement numbers AI33004 and AI34954 awarded by the National Institutes of Health. The government has certain rights to this invention.
Intracellular pathogens include, but are not limited to, Mycobacteria species including M. tuberculosis, M. avium-intracellulare (MAI), and other intracellular pathogens including Legionella pneumophila, Histoplasma capsulatum, Leishmania species including L. chagasi, L. donovani and L. major, and the like. These organisms are characterized by their ability to be phagocytosed and sequestered in macrophages in patients infected with these organisms. In general, intracellular sequestration makes these organisms more difficult to treat with standard anti-bacterial therapies.
Tuberculosis is caused principally by the pathogenic agent Mycobacterium tuberculosis (M. tuberculosis) and more rarely by M. bovis or M. africanum. M. tuberculosis is an exemplary intracellular pathogen in that it, like other intracellular pathogens is phagocytosed in vivo by mononuclear phagocytes and becomes sequestered and/or grows within the phagocytic cell. Tuberculosis continues to be a major cause of worldwide morbidity and mortality, especially in the elderly and in immunocompromised patients, such as HIV (human immunodeficiency virus)-infected persons. The World Health Organization estimates that 1.7 billion persons, or one third of the world's population, are infected with tuberculosis. New estimates indicate that there are approximately 10 million new cases of tuberculosis annually with three million deaths associated with tuberculosis worldwide.
The only current vaccine for M. tuberculosis is the BCG vaccine. This vaccine is a live attenuated strain of Mycobacterium bovis. The vaccine produces variable results and may rarely initiate active tuberculosis infection in compromised vaccinees. A significant problem associated with the vaccine is that it results in the conversion of the tuberculin skin test (PPD) from negative to positive. The tuberculin skin test is still the primary test of choice for diagnosing exposure to M. tuberculosis. Therefore, individuals receiving the BCG vaccine test positive using the tuberculin skin test making patient monitoring for M. tuberculosis exposure more difficult. Until such time that a uniformly effective vaccine exists, novel therapeutic approaches that significantly reduce the duration of therapy will have a major impact on compliance and ultimately on the transmission of this disease.
Current therapies to treat tuberculosis are becoming less satisfactory because of a growing incidence of drug-resistant strains of M. tuberculosis. Effective therapy for active tuberculosis requires multiple types of antibiotics taken for a minimum of six months. Each of these antibiotics causes sizable morbidity from drug toxicity. Further, poor compliance, in part due to the duration of treatment and side effects of the antibiotics, remains a critical issue in the treatment of tuberculosis. Improper treatment of M. tuberculosis infection has led directly to a growing incidence of multi-drug resistant tuberculosis leading to prolonged infectiousness and thereby enhanced transmission potential.
MAI is the most common mycobacterial pathogen in AIDs patients. Up to 50% of this population will develop infection due to MAI in their lifetime. MAI are inherently multi-drug resistant and treatment for these patients currently requires taking multiple types of antibiotics for life. Infections due to the other intracellular pathogens described above are also more commonly seen in the growing population of immunocompromised patients with significant morbidity and in some cases mortality. In these cases patients are also treated with multiple antimicrobial agents for a significant length of time.
The problems associated with Mycobacterium infection are also true for diseases associated with other intracellular pathogens. There is currently a need for new methods to treat intracellular pathogens such as M. tuberculosis.
Patients with cystic fibrosis are at risk for a variety of pulmonary infections, including those due to mycobacterial pathogens and also including Pseudomonas aeruginosa, (P. aeruginosa) an extracellular pathogen that chronically inhabits the airways of the lungs in these patients requiring long term antibiotic therapy. Pseudomonas aeruginosa causes significant morbidity and mortality in cystic fibrosis patients (see Fick, R. B., Jr. Chest 96:158-164, 1989 and Hoiby, N. Annu. Rev. Med. 44:1-10, 1993).